Unexpected formation of trifluoromethylated spiro or fused cyclic compounds from 4-ethyloxy-1,1,1-trifluoro-3-buten-2-one and silyl enol ethers

Article abstract of DOI:10.1055/s-2006-941574

Two kinds of trifluoromethylated spiro or fused cyclic compounds were synthesized via the unexpected direct α,α′-dialkylation of (E)-4-ethoxy-1,1,1-trifluoro-3-buten-2-one (1) with silyl enol ethers in the presence of boron trifluoride etherate. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-941574

LETTER
1343
Unexpected Formation of Trifluoromethylated Spiro or Fused Cyclic Com-
pounds from 4-Ethyloxy-1,1,1-trifluoro-3-buten-2-one and Silyl Enol Ethers
T
rifluoromethylate
u
d Spiro or
F
i
used
C
y
l
c
lic Co
i
mpoun
n
ds g Jiang, Shizheng Zhu*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road,
Shanghai 200032, P. R. of China
E-mail: zhusz@mail.sioc.ac.cn
Received 5 January 2006
fused cyclic compounds and discuss the possible mecha-
Abstract: Two kinds of trifluoromethylated spiro or fused cyclic
nism.
compounds were synthesized via the unexpected direct a,a¢-di-
alkylation of (E)-4-ethoxy-1,1,1-trifluoro-3-buten-2-one (1) with
silyl enol ethers in the presence of boron trifluoride etherate.
Although compound 1 and silyl enol ethers7 failed to react
in the absence of a catalyst, it was found that the reaction
Key words: trifluoromethylated spiro or fused cyclic compounds, proceeded smoothly in the presence of one equivalent of
silyl enol ethers, (E)-4-ethoxy-1,1,1-trifluoro-3-buten-2-one, boron
trifluoride etherate
boron trifluoride etherate. When equal amounts of silyl
enol ether 2c, derived from cycloheptanone, reacted with
1 in dichloromethane at 0 °C, there was not the expected
traditional nucleophilic addition product isolated but in-
The aldol condensation has long been recognized to be
one of the most versatile synthetic tools in organic chem-
istry.1 It is well known that silyl enol ethers can be readily
attacked by a carbonyl or an a,b-unsaturated compound in
the presence of a Lewis acid. In most of these condensa-
tion reactions an electrophile was introduced regiospecif-
ically onto one side of a silyl enol ether at the a-position.2
However, to the best of our knowledge, very little is
known about the a,a¢-dialkylation of the silyl enol ether,
although there are several related examples reported in
the literature. a,a¢-Bis(substituted-benzylidene)cycloalk-
anones and bis(trifluoroethylidene)cyclohexanone were
synthesized through the reaction of arylaldehydes and
silyl enol ether in the presence of SmI3 and ZnI2, respec-
tively.3,4 To our surprise, compound (E)-4-ethoxy-1,1,1-
trifluoro-3-buten-2-one (1) reacted with silyl enol ethers
in the presence of boron trifluoride etherate to afford, un-
expectedly, a,a¢-dialkylated products. More surprisingly,
these a,a¢-dialkylated products had spiro or fused cyclic
structures, which are difficult to synthesize by other
means. As reported in the literature, certain spiropyran
derivatives exhibited remarkable thermochromism prop-
erties.5 The interesting reversible color change of spiropy-
ran derivatives was temperature-dependent; an intense
violet color developed in polar solvents at high tempera-
ture, reverting to colorless at room temperature. Such a
characteristic has become more and more important over
the past few decades, because these compounds could be
used as thermosensors. Though several methods were
available for the preparation of these analogues, they suf-
fered from some disadvantages.6 Condensation of alde-
hydes and ketones catalyzed by traditional acids or bases
was simple but reversible. Herein, we wish to report the
unexpected formation of trifluoromethylated spiro or
stead a small quantity of 3c was observed (Scheme 1).
From the single crystal X-ray diffraction analysis of the
product 3c (Figure 1) it was clear that 3c was a bis-tri-
fluoromethylated spiropyran derivative with a completely
symmetrical framework. There was only one peak ob-
served in the 19F NMR spectrum at –72.00 ppm, which
was in agreement with its structure. Based on these exper-
imental phenomena, we surmised that there should be two
molecules of 1 participating in the reaction.
The unusual formation of the spiropyran derivative was
extremely sensitive to solvents and catalysts. First, we
examined the reaction of 1 and 2c in the presence of
BF3·OEt2 (1.0 equiv) in various solvents and the results
F3C
Si
CF3
O
O
O
BF3·OEt2
O
+
CH2Cl2, 0 °C
12 h
F3C
OEt
1
2c
3c
Scheme 1
SYNLETT 2006, No. 9, pp 1343–1346
0
1.
0
6.
2
0
0
6
Advanced online publication: 22.05.2006
DOI: 10.1055/s-2006-941574; Art ID: W00406ST
© Georg Thieme Verlag Stuttgart · New York
Figure 1 Crystal structure of compound 3c.

1344
H. Jiang, S. Zhu
LETTER
Table 2 Reaction of 1 with Silyl Enol Ethersa,9
are summarized in Table 1. It was found that the reaction
only proceeded readily in CH2Cl2. When using Et2O as the
solvent, the yield of 3c decreased to 30%. However, very
little product was found in the reaction mixture when
CH3CN or benzene was employed (Table 1, entries 5–7).
Secondly, different catalysts were examined and it was
found that other catalysts such as TiCl4, KF or CsF could
not promote this reaction and no product was obtained
(Table 1, entries 8–10). Attempting to employ catalytic
amounts of BF3·OEt2 caused a drastic decrease in the
yields (Table 1, entries 3 and 4).
Entry
1
Silyl enol ether Products
Yield (%)b
92
O
CF3
Si
O
O
F3C
3a
2a
2
3
68
71
O
CF3
Si
O
O
F3C
Table 1 Reaction of Compound 1 and 2c under Several Conditionsa
3b
2b
2c
Entry Catalyst
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
2c/1
1:1
1:2
1:2
1:2
1:2
1:2
3c (%)
37b
71b
39c
5c
F3C
CF3
1
2
BF3·OEt2 (1 equiv)
O
Si
O
O
BF3·OEt2 (1 equiv)
BF3·OEt2 (0.5 equiv)
BF3·OEt2 (0.05 equiv)
BF3·OEt2 (1 equiv)
BF3·OEt2 (1 equiv)
BF3·OEt2 (1 equiv)
TiCl4 (1 equiv)
3
3c
4
5
30c
trace
trace
–
4
5
64
67
O
CF3
Si
O
O
F3C
6
CH3CN
7
benzene 1:2
3d
2d
2e
8
CH2Cl2
CH2Cl2
CH2Cl2
1:2
1:2
1:2
F3C
9
KF (1 equiv)
–
CF3
Si
O
O
O
10
CsF (1 equiv)
–
a Reactions were carried out in solvent (5 mL) with 1, 2c, and
BF3·OEt2 under a nitrogen atmosphere at 0 °C for 12 h.
b Isolated yields.
3e
a Reactions were carried out in CH2Cl2 (10 mL), with silyl enol ether
(2 mmol), 1 (4 mmol), and BF3·OEt2 (4 mmol) under a nitrogen atmo-
sphere overnight, at 0 °C to r.t.
c According the NMR spectrum.
b Isolated yield based on the amount of silyl enol ethers employed.
A similar spiro structure was also formed when the silyl
enol ether 2e derived from pentan-3-one reacted with 1
(Table 2, entry 5). However, when two equivalents of the
six-membered ring silyl enol ether 2b was added into the
reaction mixture, there was no corresponding spiro prod-
uct obtained. The 19F NMR spectrum revealed two peaks
at –71.92 and –77.37 ppm, of equivalent intensity. Thus,
it was clear that there must be a trifluoroacetyl in its struc-
ture, and the other trifluoromethyl should connect to a
cyclic structure. Based on these data, it was clear that it
possessed a fused cyclic structure (Table 2, entry 2, 3b).
Similarly, five- or methylated six-membered ring silyl
enol ether furnished only fused cyclic compounds
(Table 2, entries 1 and 4). However, other silyl enol ethers
derived from pinacolone or a-tetralone failed to form ei-
ther the simple aldol reaction products or the polycyclic
products under the same reaction conditions. To establish
the generality of this process, we tried to employ non-
fluorinated compound (E)-1,3-diethoxy-2-propen-1-one
under the same conditions. To our disappointed, there was
no useful product isolated and most of the material de-
composed.
Although the exact mechanism for the formation of new
spiro or fused cyclic compounds is not known, we propose
that 1 undergoes a BF3·OEt2-catalyzed reaction with silyl
enol ethers to form intermediate A, which is in equilibri-
um with intermediate B. Intermediate B is attacked by a
second molecule of 1 to form C, which could undergo an
intramolecular nucleophilic reaction to form D. The inter-
mediate D could eliminate difluorohydroxyborane to
form zwitterionic intermediate E. Subsequently, when
n = 1, intramolecular electron transfer takes place and two
molecules of ethanol are eliminated to form 3a as the sole
product. This elimination of ethanol would be promoted
by the formation of a conjugated system and the strong
electron-withdrawing trifluoromethyl group.8 However,
when n = 3, an intramolecular nucleophilic reaction could
occur again followed by elimination of ethanol to form
spiro compound 3c. It is interesting to note that when sev-
en-membered and linear silyl enol ethers are employed,
the spiropyran derivatives are formed due to their lower
activation energy for cyclization. Based on the single
crystal X-ray diffraction analysis of 3c, the dihedral angle
of C5–C6–O1 and the plane of the C5¢–C6–O1¢ was 87o,
Synlett 2006, No. 9, 1343–1346 © Thieme Stuttgart · New York

LETTER
Trifluoromethylated Spiro or Fused Cyclic Compounds
1345
F
BF2
SiMe3
BF2
O
O
F–
O
O
O
A
F3C
BF3·OEt2
n
EtO
F3C
OEt
F3C
OEt
n
– Me3SiF
1
BF2
BF2
H
O
O
BF2
O
F3C
EtO
CF3
OH
HO
1
O
O
O
F3C
F3C
B
CF3
EtO
EtO
n
OEt
OEt
n
n
C
D
– F2BOH
F3C
F3C
EtO
O
O
n = 1
O
O
H
3a
CF3
CF3
– 2 EtOH
OEt
O
F3C
EtO
O
CF3
O
OEt
F3C
EtO
n
F3C
CF3
O
O
CF3
O
E
n = 3
3c
– 2 EtOH
OEt
Scheme 2 Proposed mechanism for forming compound 3a and 3c.
almost a right angle. Seven-membered or linear silyl enol
ether could easily form spiropyran structures without in-
creasing the strain energy significantly. On the other hand,
spiropyran structures formed from the five- and six-mem-
bered ring silyl enol ethers may have high strain energy,
prohibiting their formation. Therefore, fused cyclic prod-
ucts 3a, 3b, and 3e are favored.
References and Notes
(1) Mukaiyama, A.; Banno, K.; Narasaka, K. J. Am. Chem. Soc.
1974, 96, 7503.
(2) (a) Matsugi, M.; Murata, K.; Gotanda, K.; Nambu, H.;
Anilkumar, G.; Matsumoto, K.; Kita, Y. J. Org. Chem. 2001,
66, 2434. (b) Loh, T.-P.; Wei, L.-L. Tetrahedron 1998, 54,
7615. (c) Crane, S. N.; Burnell, D. J. J. Org. Chem. 1998, 63,
1352. (d) Pryor, W. A.; Giamalva, D.; Church, D. F. J. Am.
Chem. Soc. 1985, 107, 2797.
(3) Bao, W. L.; Zhang, Y. M.; Ying, T. K. Synth. Commun.
1996, 26, 503.
(4) Kubota, T.; Iijima, M.; Tanaka, T. Tetrahedron Lett. 1992,
33, 1351.
(5) Koelsch, C. F. J. Org. Chem. 1951, 16, 1362.
(6) (a) Lowenbein, A.; Katz, W. Ber. Dtsch. Chem. Ges. 1926,
59, 1377. (b) Dickinson, R.; Heilbron, I. M. J. Chem. Soc.
1927, 1699. (c) Gawronski, J.; Gawronska, K.; Katrusiak, A.
Tetrahedron 1989, 45, 6875.
(7) Silyl enol ethers can be conveniently synthesized from
ketones: Cazeau, P.; Duboudin, F.; Moulines, F.; Babor, O.;
Dunogues, J. Tetrahedron 1987, 43, 2075.
(8) (a) Takahashi, M.; Nagaoka, H.; Inaue, K. J. Heterocycl.
Chem. 2004, 41, 525. (b) Pavlik, J. W.; Ayudhya, T. I. N.;
Tantayanon, S. J. Heterocycl. Chem. 2003, 40, 1087.
(c) Pavlik, J. W.; Ayudhya, T. I. N.; Tantayanon, S. J.
Heterocycl. Chem. 2002, 39, 2913. (d) Peng, W. M.; Zhu, S.
Z. J. Fluorine Chem. 2002, 116, 81. (e) Song, L. P.; Chu, Q.
L.; Zhu, S. Z. J. Fluorine Chem. 2001, 107, 107. (f) Zhu, S.
Z.; Jin, G. F.; Peng, W. M.; Huang, Q. C. Tetrahedron 2003,
59, 2899.
In summary, two kinds of unexpected trifluoromethylated
products are obtained in good yields through the reaction
of (E)-4-ethoxy-1,1,1-trifluoro-3-buten-2-one with silyl
enol ethers under very mild conditions. Seven-membered
and linear silyl enol ethers give the spiropyran derivatives,
while six-, and five-membered silyl enol ethers form
fused cyclic compounds, which are difficult to synthesize
by other methods. This unusual transformation may have
great potential in synthesis, complementing the existing
methods for the synthesis of the substitutional spiro or
fused compounds. Further studies to develop new ana-
logues are underway in our laboratories.
Acknowledgment
Financial support for this project was provided by The National
Natural Science Foundation of China (NNSFC) (Nos. 20472106
and 20532040).
(9) General Procedure. BF3·OEt2 (1.6 mL, 6 mmol) was added
dropwise to a mixture of 1 (1.01 g, 6 mmol) and silyl enol
ether (3 mmol) in CH2Cl2 (5 mL) at 0 °C under a nitrogen
atmosphere. After 12 h TLC analysis showed the reaction
was complete. H2O (10 mL) was added to the reaction
Synlett 2006, No. 9, 1343–1346 © Thieme Stuttgart · New York

1346
H. Jiang, S. Zhu
LETTER
mixture to quench the reaction, and then the organic layer
was extracted with CH2Cl2 and dried over Na2SO4. The
residue was subjected to column chromatography on silica
gel (hexane–EtOAc, 60:1) to provide pure products.
(E)-1,1,1-Trifluoro-4-(2-trifluoromethyl-5,6-dihydro-
cyclopenta[b]pyran-7-yl)but-3-en-2-one(3a):Yield:92%;
red solid; mp 88–89 °C. IR: 2976, 1687, 1587, 1515, 1252,
1078, 1018, 834 cm–1. 1H NMR (CDCl3): d = 7.95 (1 H, d,
3JHH = 15.0 Hz, CH), 6.21 (1 H, d, 3JHH = 6.3 Hz, CH), 6.20
(1 H, d, 3JHH = 15.0 Hz, CH), 6.10 (1 H, d, 3JHH = 6.3 Hz,
CH), 2.71 (2 H, m, CH2), 2.69 (2 H, m, CH2). 13C NMR
(CDCl3): d = 174.9 (C3¢, 2JCF = 34.7 Hz), 159.99 (C4a),
146.02 (C7a), 142.5 (C2, 2JCF = 38.8 Hz), 139.31 (C4), 118.8
(C1¢¢, 1JCF = 271.5Hz), 116.8 (C4¢, 1JCF = 292.5 Hz), 116.22
(C7), 115.78 (C2¢), 112.88 (C3), 107.50 (C1¢), 25.49 (C6),
24.89 (C5). 19F NMR (CDCl3, CHF3 as internal standard):
d = –71.12, –77.18 (s, CF3). LRMS: m/z (%) = 310 (M+,
64.38), 291 (M+ – F, 4.69), 263 (1.33), 241 (M+ – CF3, 100),
213 (M+ – COCF3, 17.80), 115 (30.22), 69 (CF3, 8.09). Anal.
Calcd for C13H8F6O2 (310.195): C, 50.33; H, 2.60. Found: C,
49.98; H, 2.68.
(E)-1,1,1-Trifluoro-4-(2-trifluoromethyl-6,7-dihydro-
5H-1-benzopyran-8-yl)but-3-en-2-one (3b): Yield: 68%;
red solid; mp 99–101 °C. IR: 2925, 1689, 1533, 1307, 1143
cm–1. 1H NMR (CDCl3): d = 8.22 (1 H, d, 3JHH = 15.3 Hz,
CH), 6.31 (1 H, d, 3JHH = 15.6 Hz, CH), 6.20 (2 H, s, CH),
2.54 (2 H, t, 3JHH = 5.7 Hz, CH), 2.45 (2 H, t, 3JHH = 6 Hz,
CH2), 1.81 (2 H, m, CH2). 13C NMR (CDCl3): d = 179.2 (C3¢,
2JCF = 33.6 Hz), 155.3 (C4a), 143.9 (C2, 2JCF = 38.5 Hz),
142.8 (C8a), 134.7 (C4), 122.1 (C8), 116.9 (C1¢¢, 1JCF = 269.6
Hz), 116.9 (C4¢, 1JCF = 288.8 Hz), 112.5 (C2¢), 110.6 (C3),
105.7 (C1¢), 29.7 (C7), 24.4 (C5), 19.7 (C6). 19F NMR (CDCl3,
CHF3 as internal standard): d = –71.92, –77.37. LRMS: m/z
(%) = 324 (M+, 29.59), 305 (M+ – F, 2.33), 255 (M+ – CF3,
100), 199 (7.47), 69 (CF3, 13.18). HRMS: m/z calcd for
C14H10F6O2: 324.059; found: 324.062.
(CF3, 1JCF = 271.8 Hz), 120.28 (C8,9), 103.46 (C13), 102.69
(C3,10), 33.423 (C7,6), 31.81 (C5,8). 19F NMR (CDCl3, CHF3
as internal standard): d = –72.00 (s, CF3). LRMS: m/z (%) =
338 (M+, 27.94), 319 (M+ – F, 3.27), 291 (3.98), 269 (M+ –
CF3, 100), 115 (11.52), 69 (CF3, 5.64). Anal. Calcd for
C15H12F6O2 (338.248): C, 53.26; H, 3.57. Found: C, 53.18;
H, 3.57. X-ray data C15H12F6O2: FW = 338.25; temperature
293 K; monoclinic,C2/c; wavelength 0.71 Å; a = 14.504 (4)
Å, b = 13.383 (4) Å, c = 9.806 (3) Å, a = 90o, b = 130.413
(34)o, g = 90o; V = 1449.2 (8) Å3; Z = 4, Dc = 1.550 mg/m3;
absorption coefficient 0.153 mm–1; F(000) = 688; size 0.515
× 0.371 × 0.128 mm; 2.39<q<27.00; reflections collected
4052; absorption correction empirical; transmission 1.00mix
– 0.602min; goodness-of-fit on F2 1.026; final R indices
R1 = 0.0518, wR2 = 0.1294.
(E)-1,1,1-Trifluoro-4-(7-methyl-2 trifluoromethyl-6,7-
dihydro-5H-1-benzopyran-8-yl)but-3-en-2-one (3d):
Yield: 64%; colorless solid; mp 70–72 °C. IR: 3096, 1689,
1534, 1142 cm–1. 1H NMR (CDCl3): d = 8.20 (1 H, d,
3JHH = 15.6 Hz, CH), 6.30 (1 H, d, 3JHH = 15.0 Hz, CH), 6.21
(2 H, m, CH), 2.55 (2 H, m, CH2), 2.50 (1 H, m, CH2), 2.05
(1 H, m, CH2), 2.00 (1 H, m, CH2), 1.08 (3 H, d, 3JHH = 6.3
Hz, CH3). 13C NMR (CDCl3): d = 179.7 (C3¢, 2JC-F = 30 Hz),
152.2 (C4a), 143.7 (C2, 2JCF = 38.5 Hz), 142.8 (C8a), 134.5
(C4), 122.1 (C8), 116.7 (C1¢¢, 1JCF = 269.4 Hz), 116.5 (C4¢,
1JCF = 288.6 Hz), 112.6 (C2¢), 111.3 (C3), 105.4 (C1¢), 37.5
(C7), 32.6 (C5), 26.1 (C6), 20.7 (CH3). 19F NMR (CDCl3,
CHF3 as internal standard): d = –71.85, –77.39 (s, CF3).
LRMS: m/z (%) = 338 (M+, 32.12), 319 (M+ – F, 2.78), 269
(M+ – CF3, 100), 270 (16.35), 69 (CF3, 11.55). Anal. Calcd
for C15H12F6O2 (338.248): C, 53.26; H, 3.58. Found: C,
53.26; H, 3.84.
5,5¢-Dimethyl-2,2¢-trifluoromethyl-6,6¢-spirobis-
dihydropyra (3e): Yield: 67%; red solid; mp 109–110 °C.
IR: 2998, 1688, 1347, 1306, 1187, 1061, 911, 838 cm–1. 1H
NMR (CDCl3): d = 6.18 (2 H, d, 3JHH = 5.1 Hz, CH), 5.96 (2
H, d, 3JHH = 6 Hz, CH), 1.92 (6 H, s, CH3). 13C NMR
2,11-Ditriflouromethyl-5,6,7,8-
2
tetrahydrocyclohepta[1,2-b;1,7-b]di(dihydropyran)(3c):
Yield: 71%; colorless solid; mp 123–125 °C. IR: 2948,
1683, 1449, 1349, 1306, 1189, 1070 cm–1. 1H NMR
(CDCl3): d = 6.22 (2 H, d, 3JHH = 6.3 Hz, CH), 6.05 (2 H, d,
3JHH = 6.3 Hz, CH), 2.48 (2 H, m, CH2), 2.34 (2 H, m, CH2),
2.03 (2 H, m, CH2), 1.48 (2 H, m, CH2). 13C NMR (CDCl3):
d = 137.43 (C2,11, 2JCF = 37.7 Hz), 134.28 (C4a,8a), 119.54
(CDCl3): d = 138.69 (C2,10, JCF = 36.5 Hz), 128.5 (C5,7),
119.94 (CF3, 1JCF = 269.6 Hz), 120.28 (C4,8), 109.46 (C6),
101.21 (C3,9), 43.41 (CH3). 19F NMR (CDCl3, CHF3 as
internal standard): d = –72.19 (s, CF3). LRMS: m/z (%) =
312 (M+, 86.06), 297 (29.52), 265 (9.90), 245 (100), 215
(30.13), 146 (35.40), 69 (30.27). Anal. Calcd for C13H10F6O2
(312.210): C, 50.01; H, 3.28. Found: C, 49.71; H, 3.30.
Synlett 2006, No. 9, 1343–1346 © Thieme Stuttgart · New York